The invention relates to comparing biopolymer sequences. Nucleic acids and proteins are two types of biopolymers that have complex sequences. Nucleic acids are polymers composed of a sequence of nucleotides. At a given position, one of four nucleotides can be present. One function of nucleic acids is to encode polypeptides.
Polypeptides are polymers composed of a sequence of amino acids. At a given position, one of twenty amino acids can be present. The sequence of amino acid in a polypeptide chain determines the structural fold that the polypeptide prefers to adopt. The properties of each amino acid side chain are unique and varied. Relevant properties for structure and function include hydrophobicity, size, charge, and rotamer preference.
For analysis, polymer chains are typically represented as a string of alphabetical characters, each character abbreviating the identity of a monomer in the chain. It is known to classify biopolymer sequences by their similarity to characterized sequences. Function is then imputed on the basis of the classification. For example, a sequence that is 70% identical to a protease and is 100% identical at residues demonstrated to mediate the enzymatic function of proteases is likely form a compound with protease activity.
Determining similarity for protein sequences is nontrivial for at least the following reasons. First, similar protein sequences can include insertions or deletions that shift the frame of comparison. Second, whereas two identical amino acids at a given position are clearly similar, measures of similarity of any two non-identical amino acids can fall within a large range. Further, the same pair of non-identical amino acids that function similarly in one context, may not in another context.
A variety of computer-based techniques have been developed to compare protein sequences. For example, the BLAST algorithm (Basic Local Alignment Search Technique; e.g., described by Altschul, et al. (1990) J. Mol. Biol. 215:403–10) allows for gaps of various sizes. A scoring scheme penalizes gaps, the enlargement of gaps, and non-identity. Further, a matrix that describes all possible pairs of amino acids at a given position is used to determine the extent of non-similarity at the position.
It is also possible to compare a biopolymer sequence to a profile of a family of similar sequences. This comparison can be made using an implementation of a Hidden Markov Model (HMM). Profile HMMs are a class of probabilistic models particularly adept for profile searches of biological sequences (Churchill (1989) Bull. Math. Biol. 51:79–94; Krogh et al. (1994) J. Mol. Biol. 235:1501–1531; Hughey and Krogh (1996) Computer Applications in the Biosciences 12:95–107; Eddy et al. (1995) J. Comp. Biol. 2:9–23; Durbin et al. (1998) Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids Cambridge University Press; Gribskov et al. (1987) Proc. Natl. Acad. Sci. USA 84:4355–58). Profile HMMs include a network of nodes. Nodes are used to indicate the probability of a given monomer at a particular sequence position “emit” monomers at particular sequence positions. The probability depends on the frequency of the given monomer at the particular position in the family of similar sequences. Traversal of a path across the network of nodes of a profile HMM produces a single sequence that a likely family member.